Herpes Simplex Viruses (HSV) and HSV Infections
Herpes simplex virus 2 (HSV-2) is the primary cause of genital ulcer disease. It can cause both an acute, productive infection and a long-term latent infection characterized by unpredictable periodic recurrences (66). Apart from causing lifelong, recurrent genital ulcers, HSV infections are a major concern in AIDS patients. It has been documented that genital HSV-2 infection triples the risk for sexually acquiring HIV infection (20), and in Africa, this increase in risk may contribute to 25-35% of incident HIV infections (1).
Although the severity and duration of most symptomatic HSV primary infections can be reduced by oral or intravenous treatment with acyclovir, valacyclovir, or famciclovir, antiviral therapy neither prevents the establishment of latent infection from primary infection nor reduces subsequent recurrences (66). The continued spread of genital herpes in the United States over the past two decades (19) and the increasing incidence of HSV resistant to current antiviral medications suggest that there is a need for safe and efficacious vaccines against HSV infections (31, 60). In addition, the finding that HSV suppressive therapy leads to a significant reduction in levels of HIV in the genital mucosa and plasma of women infected with both HSV-2 and HIV (52) suggests that an effective HSV vaccine may also have major implications in control of HIV infection (1, 31).
HSV-2 Glycoprotein D (gD2)
HSV glycoprotein D (gD) is one of the most predominant viral antigens expressed on the surface of infected cells (21) and as well as on the viral envelope (24). gD is essential for the entry of the virus into cells and is a major target for neutralizing antibodies against HSV infection (12, 49, 53). Moreover, gD is the predominant viral target for CD4+ T cells including CD4+ T cell cytotoxicity and CD8+ T cells in human and murine models of HSV infection (27, 28, 30, 34, 47, 65, 75). For these reasons, gD has been a major focus for HSV subunit vaccine development (32, 60).
In a phase 3 clinical trial, Stanberry, et al., showed that vaccination with recombinant gD from HSV-2 (gD2), in combination with adjuvant AS04, provided 73-74% efficacy in protecting against the development of genital herpes disease in HSV-seronegative women (62). No significant efficacy was observed, however, in men and in subjects who were seropositive for HSV-1. Although gD2-specific humoral and CD4+ T cell responses were detected in the immunized hosts, it is not clear whether gD2/AS04 was effective in eliciting a CD8+ T cell response (31, 32). This study suggests that there is a need for an HSV vaccine that elicits a broader humoral, as well as CD4 and CD8 T-cell, response to both gD2 and other HSV viral antigens (29, 31, 32).
Viral Vaccines
It is well documented that live viral vaccines capable of de novo synthesis of immunogens in the host induce a broader and more durable immune response than vaccines consisting of only peptides or proteins. Various forms of replication-defective HSV and neuroattenuated, replication-competent mutants have been developed and tested as potential in vaccines against HSV infection (U.S. Pat. No. 7,223,411; (18)).
Because both replication-defective viruses and neuroattenuated mutants can co-replicate with wild-type virus or become replication-competent in the context of wild-type virus, their use as a vaccine in humans poses a safety concern, particularly in individuals who harbor latent HSV infection (33). The observation that replication-defective HSV-1 mutants can reactivate the latent HSV-1 immediate-early promoter in the rodent brain has raised additional safety concerns about the possibility of such recombinants triggering outbreaks of productive viral infections in latently infected individuals (63). Thus, a desirable replication-defective recombinant HSV vaccine should not only possess the ability to express a broad spectrum of virus-encoded antigens but should also encode a unique function that can prevent lytic infection of wild-type HSV when encountered within the same cells. Such a safety mechanism would minimize the potential outbreak of the vaccine virus caused by the recombination of the vaccine vector with wild type virus in the host.